The rationale for combination versus single-entity therapy in hypertension

The rationale behind combination therapy relates to the fact that when two different classes of agents are combined, they may provide complementary, additive, or synergistic antihypertensive effects through different mechanisms. Lower doses of two drugs, which provide blood pressure reduction similar to higher doses of one drug, may enhance tolerability and improve compliance. Investigative efforts have been undertaken to explore fixed-dose combinations of drugs that do not include diuretics. The first nondiuretic fixed-dose combinations are an angiotensin-converting enzyme (ACE) inhibitor-calcium antagonist combination or a β-blocker-calcium antagonist combination. The rationale for an ACE inhibitor-calcium antagonist combination is based on the fact that both drugs reduce vasoconstriction through different mechanisms. The ACE inhibitor largely attenuates vasoconstriction through augmentation of vasodilatory kinins and reduction of the vasoconstrictive effect of angiotensin II, whereas the calcium antagonists, through attenuating the transmembrane flux of calcium, inhibit calcium-mediated electromechanical coupling in contractile tissue in response to numerous stimuli. Moreover, both classes of drugs facilitate salt and water excretion by the kidney through different mechanisms. The ACE inhibitor restores the renal-adrenal response to salt loading, whereas the calcium antagonist possesses intrinsic natriuretic properties through poorly described mechanisms of inhibiting renal tubular salt and water reabsorption. The combination of a β-blocker and dihydropyridine calcium antagonist is logical due to the different antihypertensive mechanisms of these drugs without risk of cardiac conduction abnormalities. There is evidence in clinical trials that ACE inhibitors may offset one of the major side effects associated with calcium antagonist therapy: pedal edema. Although the studies are small and the observations subjective, there is consistent evidence that the combination may provide an opportunity to reduce the likelihood of this common clinical problem. There is also evidence of reduced calcium antagonist-associated constipation and headache with this type of drug combination, likely because lower doses of this agent are used in combination with ACE inhibitors. However, there is no published evidence that calcium antagonists reduce the cough associated with the ACE inhibitor.